Since protein kinases which phosphorylate specific amino acids of proteins, are closely involved in various signal transduction in cells and disease mechanisms, inhibition of such kinases have been an important therapeutic target.
The protein kinases represent a large group of proteins playing critical roles in regulating various cellular processes for maintenance and control of cellular functions. They include abl, Akt, AXL, bcr-abl, Blk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSFlR, CSK, DDR1, DDR2, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, flt-3, flt-4, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes and Zap70.
It is known that some protein kinases are closely related to uncontrolled vascularization, such asocular neovascularization, retinopathy (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, angioma, arteriosclerosis, inflammatory diseases, such as a rheumatoid, rheumatic inflammatory diseases including rheumatoid arthritis, or other chronic inflammatory diseases such as chronic asthma, post-transplantation atherosclerosis, endometriosis, and other neoplastic diseases, including solid tumor and liquid tumor. With regard to a lot of pathological disorders and diseases during embryonic development and normal growth, an angiogenic factor known as vascular endothelial growth factor (VEGF, originally known as “vascular permeability factor (VPR)”) and its receptor play a critical role in the regulation of growth and differentiation of the vascular system and its components.
VEGF is a disulfide-linked, 46-kDa dimeric glycoprotein related to “platelet-derived growth factor (PDGF)”. It is produced in normal and tumor cells, is an endothelial cell-specific mitogen, exhibits angiogenic activity in in vivo tests (e.g. in the rabbit cornea), is chemotactic for endothelial cells and monocytes, and induces plasminogen activating factor in endothelial cells, which is involved in degradation of protein in the cellular matrix during neovascularization of capillary vessels. A number of VEGF isoforms are known that exhibit biological activity comparable to VEGF but are secreted from different cells and have different heparin-binding abilities. Further, “placental growth factor (PlGF)” and VEGF-C are included in the VEGF family.
VEGF receptors (VEGFR) are transmembranous receptors of tyrosine kinase. They are characterized by seven extracellular immunoglobulin-like domains and an intracellular tyrosine kinase domain. Several VEGF receptors, such as VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR) and VEGFR-3 are known.
In a lot of human tumors, especially in glioma and carcinomas, VEGF and VEGF receptors are expressed in high levels. This has led to the hypothesis that the VEGF released by tumor cells stimulates the growth of blood capillaries and proliferation of tumor endothelium in a paracrine manner and, through the improved blood supply, accelerates the tumor growth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with glioma. A direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo is shown in studies in which VEGF expression or VEGF activity was inhibited.
Angiogenesis is regarded as a necessary requirement for tumors to grow beyond a diameter of about 1-2 mm. Up to this limit, oxygen and nutrients may be transported to the tumor cells by diffusion. Every tumor, regardless of its origin and cause, is thus dependent on angiogenesis for its growth after it has reached a certain size.
Three principal mechanisms are important in the activity of angiogenesis inhibitors against tumors. They are: 1) inhibition of the growth of vessels, especially capillary vessels, into avascular resting tumors, with the result that there is no net tumor growth because of the balance that is activated between cell death and proliferation; 2) prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; and 3) inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the blood vessels.
It is known that VEGFs are the only angiogenic growth factors contributing vascular hyperpermeability and the formation of edema. In fact, vascular hyperpermeability and edema appear to be mediated via VEGF production.
VEGF-mediated hyperpermeability can significantly contribute to disorders with excessive matrix deposition, aberrant stromal proliferation, fibrosis, and so forth. Therefore, regulators of angiogenesis have become an important therapeutic target.
Hepatocyte growth factor (HGF) also known as scatter factor plays an important role in the regeneration of liver cells. HGF is a mesenchyme-derived cytokine known to induce multiple pleiotropic responses in normal and neoplastic cells result in proliferation in both epithelial and endothelial cells, dissociation of epithelial colonies into individual cells, stimulation of motility (motogenesis) of epithelial cells, cell survival, induction of cellular morphogenesis, promotion of invasion, and all critical processes underlying metastasis. It is also reported that HGF promotes angiogenesis, and that it plays a critical role in tissue regeneration, wound healing and normal embryonic processes, all of which are dependent on both cell motility and proliferation.
Those physiological processes are initiated by HGF through high-affinity binding to its receptor, c-Met, an identified proto-oncogene. The ligand binding induces c-Met dimerization that results in an autophosphorylated activated receptor. Activation of c-Met promotes signal transduction cascades of transphosphorylation of key cytoplasmic tyrosine residues responsible for recruiting multiple effector proteins including the p85 subunit of PI3-kinase, phospholipase Cγ, Grb2 and Shc adaptor proteins, the protein phosphatase SHP2 and Gab1. Activation of other signaling molecules has been reported in HGF-stimulated cells, most notably Ras, MAP kinase, STAT, ERK-1, -2 and FAK which are involved in cell proliferation.
c-Met, also known as hepatocyte growth factor receptor (HGFR), is a membrane receptor molecule located in epithelial cells. It plays a critical role in the regulation of cell motility. HGF/SF is secreted in the liver, as well as in the lungs, kidneys and heart, when the organs are damaged. c-Met is expressed predominantly in epithelial cells but has also been identified in endothelial cells, myoblasts, hematopoietic cells and motor neurons. Overexpression of HGF and activation of c-Met have been associated with the onset and progression of a number of different tumor types as well as the promotion of metastatic diseases.
HGF and c-Met are overexpressed in various solid tumors, liver cancer, breast cancer, pancreatic cancer, lung cancer, renal cancer, bladder cancer, ovarian cancer, brain tumor, prostate cancer, gallbladder cancer, myeloma and many other diseases. Mutations of c-Met have also been identified in ovarian cancer, childhood HCC, gastric carcinoma, head and neck squamous cell carcinoma, non-small cell lung carcinoma and colorectal metastasis. In addition, further evidence supporting the role of c-Met in cancer is based on the overexpression of HGF and c-Met receptor in various tumors including thyroid, ovarian and pancreatic carcinomas. It has also been demonstrated to be amplified in liver metastasis of colorectal carcinoma. Generally, most human tumors and tumor cell lines of mesenchymal origin inappropriately express HGFR and/or HGF.
Numerous experimental data have demonstrated the role of HGF and c-Met in tumor invasion, growth, survival and progression ultimately leading to metastasis. In preclinical studies, transgenic expression of HGF results in a metastatic phenotype, and an amplified/overexpression c-Met spontaneously transforms NIH-3T3 cells. In addition, biological agents, such as ribozymes, antibodies and antisense RNAs targeting either HGF or c-Met have been shown to inhibit tumorigenesis. In this regard, the contents of Korean Patent Publication No. 10-2008-0004617 are incorporated hereto in its entirety by reference.
Thus, selective, small molecule kinase modulators targeting c-Met are expected to have therapeutic potential for the treatment of cancers in which c-Met receptor activation plays a critical role in the development and progression of primary tumors and secondary metastases. HGF is also known to regulate angiogenesis, a process critical in tumor growth and dissemination. Therefore, there is a potential for this class of modulators to impact angiogenesis-dependent diseases as well that may include, among others, diabetic retinopathy, macular degeneration, obesity and inflammatory disease such as rheumatoid arthritis.
Considering the role of HGF and/or c-Met, it is important to substantially suppress or inhibit the biological effect of HGF and/or its receptor in order to improve the aforesaid diseases or pathological conditions. Thus, a compound inhibiting HGF will be a useful compound. The compounds presented herein have never been described in regard to treatment of cancer as angiogenesis inhibitors nor treatment of cancer as c-Met inhibitors.